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Synergizing radiotherapy and immunotherapy: Current challenges and strategies for optimization.

ABSTRACT: Numerous clinical studies are investigating the integration of radiotherapy and immune checkpoint inhibitors (ICI) in the management of advanced or metastatic solid cancers based on preclinical evidence demonstrating a synergistic interaction between these treatments. However, it remains unclear how to optimally integrate these therapeutic modalities in the treatment of cancer patients. Beyond disease-specific factors there exists numerous unanswered questions regarding optimal sequencing of radiation and ICI, as well as, radiation dosing and target selection. Here, we examine the available clinical evidence for combination radiation and ICI approaches and propose strategies to expand investigations of the potential synergy in cancer patients.

SUBMITTER: Rajeev-Kumar G

PROVIDER: S-EPMC9798173 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Synergizing radiotherapy and immunotherapy: Current challenges and strategies for optimization.

Rajeev-Kumar Greeshma G Pitroda Sean P SP

Neoplasia (New York, N.Y.) 20221221

Numerous clinical studies are investigating the integration of radiotherapy and immune checkpoint inhibitors (ICI) in the management of advanced or metastatic solid cancers based on preclinical evidence demonstrating a synergistic interaction between these treatments. However, it remains unclear how to optimally integrate these therapeutic modalities in the treatment of cancer patients. Beyond disease-specific factors there exists numerous unanswered questions regarding optimal sequencing of rad ...[more]

PMID: 36563632

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Project description:Lung cancer is the leading cause of cancer-related deaths worldwide. Immune checkpoint inhibitors, including monoclonal antibodies against programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1), have dramatically improved the survival and quality of life of a subset of non-small cell lung cancer (NSCLC) patients. Multiple predictive biomarkers have been proposed to select the patients who may benefit from the immune checkpoint inhibitors. EGFR-mutant NSCLC is the most prevalent molecular subtype in Asian lung cancer patients. However, patients with EGFR-mutant NSCLC show poor response to anti-PD-1/PD-L1 treatment. While small-molecule EGFR tyrosine kinase inhibitors (TKIs) are the preferred initial treatment for EGFR-mutant NSCLC, acquired drug resistance is severely limiting the long-term efficacy. However, there is currently no further effective treatment option for TKIs-refractory EGFR-mutant NSCLC patients. The reasons mediating the poor response of EGFR-mutated NSCLC patients to immunotherapy are not clear. Initial investigations revealed that EGFR-mutated NSCLC has lower PD-L1 expression and a low tumor mutational burden, thus leading to weak immunogenicity. Moreover, the use of PD-1/PD-L1 blockade prior to or concurrent with osimertinib has been reported to increase the risk of pulmonary toxicity. Furthermore, emerging evidence shows that PD-1/PD-L1 blockade in NSCLC patients can lead to hyperprogressive disease associated with dismal prognosis. However, it is difficult to predict the treatment toxicity. New biomarkers are urgently needed to predict response and toxicity associated with the use of PD-1/PD-L1 immunotherapy in EGFR-mutated NSCLC. Recently, promising data have emerged to suggest the potentiation of PD-1/PD-L1 blockade therapy by anti-angiogenic agents and a few other novel therapeutic agents. This article reviews the current investigations about the poor response of EGFR-mutated NSCLC to anti-PD-1/PD-L1 therapy, and discusses the new strategies that may be adopted in the future.

Project description:IntroductionWith the introduction of tyrosine kinase inhibitors and systemic antibodies, including immune checkpoint inhibitors, the survival of advanced-stage cancer patients has improved for many tumor types. These patients are increasingly referred for radiotherapy, but it is unclear whether radiotherapy combined with these drugs is safe. No international guidelines exist on whether or how to combine these drugs with radiotherapy. Therefore, we investigated the current clinical practice in the Netherlands regarding hypofractionated radiotherapy in patients using targeted drugs and immunotherapy.Materials and methodsWe sent a survey to all 21 Dutch radiotherapy institutes. Dedicated radiation oncologists, medical oncologists and pulmonologists were asked to fill out the survey. The questions explored their familiarity with the combination of targeted drugs and immunotherapy with radiotherapy, the encountered clinical difficulties and factors influencing treatment decisions.ResultsThe survey was filled out by 54 respondents from 19 different institutes. The median annual number of patients per radiation oncologist referred for radiotherapy when using targeted drugs or immunotherapy was 10 and 15, respectively. Despite this high number, only 11% of the radiation oncologists stated that they had sufficient information (resources) for adequate treatment decision making. Among all physicians, 44% stated that there was insufficient knowledge within their institute regarding this topic. Only 17% stated that there was a multidisciplinary protocol available. The application of radiotherapy treatment adaptations (technique, dose, fractionation, field size) varied widely. Generally, there seemed to be no consensus regarding the expected toxicity of combined drug-radiotherapy treatments and the expected risk of tumor flare upon temporary drug discontinuation.ConclusionThere is no consensus amongst involved medical specialties on expected toxicity. Consequently, it is necessary to perform clinical studies examining the safety of combined drug-radiotherapy treatments, to add radiotherapy to phase I-III clinical trials for new drugs and to incorporate outcomes into multidisciplinary, evidence-based guidelines.

Dataset Information

Synergizing radiotherapy and immunotherapy: Current challenges and strategies for optimization.

Publications

Synergizing radiotherapy and immunotherapy: Current challenges and strategies for optimization.

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